Design and development of novel tools for the screening and identification of inhibitors of HER receptor family and NFR2 for ovarian cancer therapy

Cancer, which is characterised by aggressiveness and increased capacity for metastatic spread still requires basic researchers and clinicians to direct enormous efforts toward the development of novel therapeutic targets. Potential novel targets can be identified and exploited in combination with currently existing therapeutic approaches to improve their efficacy and overcome treatment resistance of tumour cells, protecting the patient from recurrence. To achieve this, different strategies and techniques can be proposed to identify the most promising candidate molecules for further exploitation as therapeutic targets. Human epidermal growth factor receptors (HERs) and NF-E2-related factor 2 (NRF2) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents. Nevertheless, there is limited understanding of the regulation of HER expression and activation, and the link between NRF2 and HER signalling pathways. This research has demonstrated that pharmacological activation of NRF2 by tert-butyl hydroquinone (tBHQ) upregulates the expression of HER family receptors, HER1 and HER4, elevates phospho protein kinase B (pAKT) levels, and enhances the proliferation of ovarian cancer cells. Pharmacological inhibition using retinoic acid (RA) and bexarotene and genetic inhibition using small interfering RNA (siRNA), did the opposite. Further, tBHQ caused transcriptional induction of HER1 and HER4 with different levels of expression, while siRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression. A panel of potent NRF2 inhibitors were screened with the hope of finding the most potent for further investigation. Bexarotene was found to be the most potent and was used either alone, or in combination with lapatinib or erlotinib. The use of these drugs in combination with bexarotene resulted in the repression of HER1, HER2, HER3 and HER4 expression, inhibition of NRF2, elevation of ROS, depletion of glutathione and enhanced cytotoxicity in PEO1, OVCAR3, SKOV3 and MCF7-AREc32 cell lines. This explained the crosstalk mechanism between HER receptor family and NRF2 and the role of NRF2 in drug resistance and as a relevant anti-cancer target which opens up novel avenues of targeting HER receptor kinase family and NRF2 pathways for improving cancer therapy.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

Abertay University

Year dc:date.issued

2017

Author dc:creator

• Hamza Kankia, Ibrahim

Advisors dc:contributor.advisor

• Moult, Peter
• Deeni, Yusuf

• EGFR/HER family
• NRF2
• ROS
• HER targeted inhibitors
• Ovarian cancer

Language dc:language

eng

Identifier

oai:rke.abertay.ac.uk:studenttheses/441e2039-1bde-448b-9c87-d2845ac1da96

OAI identifier oai:identifier

oai:rke.abertay.ac.uk:studenttheses/441e2039-1bde-448b-9c87-d2845ac1da96